The 2021 European Society for Medical Oncology (ESMO) clinical guidelines have recommended the application of extended pleurectomy/decortication (ePD) as a surgical approach for malignant pleural mesothelioma (mPM).¹ Notwithstanding the recommendation, the MARS2 study, a multicentre, randomized trial, was conducted to compare pleurectomy decortication ePD and chemotherapy (CT) with CT alone among patients with PM.² Ironically, EPD was associated with worse patient outcomes, including an elevated risk of mortality, complications, and deterioration in quality of life (QoL).²

Surgical approaches have always played an important role in the management of mPM.¹ The treatment algorithm for mPM in the 2021 ESMO guidelines had recommended the use of video-assisted thoracic surgery (VATS) and macroscopic complete resection as the first and second surgical options respectively.¹ In particular, ePD is considered a favored approach for macroscopic complete resection.¹ A systematic review comparing the clinical efficacy between ePD and extrapleural pneumonectomy (EPP), a conventional surgical approach, had established that ePD was associated with significantly lower perioperative mortality (2.9% vs. 6.8%, p=0.02) and morbidity (27.9% vs. 62.0%, p<0.0001) than EPP, thus affirming ePD as a superior surgical option.³ Nevertheless, a comparison between patient outcomes of ePD and no-surgery approaches remains unexplored, given that multiple retrospective studies suggested additional survival benefits for patients undergoing surgery.¹

The MARS2 study was commenced to investigate the clinical efficacy of ePD plus CT and compare it with that of CT monotherapy in patients with mPM.² A total of 355 adult patients with mPM were recruited between June 2015 and January 2021.² The patients first received 2 cycles of first-line platinum CT and were then randomized 1:1 into either receiving ePD surgery plus 4 cycles of adjuvant platinum CT (n=169) or 4 cycles of platinum CT alone (n=166).² After randomization, a total of 7.5% of patients withdrew from the study.² Overall survival (OS) served as the primary endpoint of this study, while secondary endpoints included progression-free survival (PFS), safety and health-related QoL.²

When compared to CT alone, the combination of ePD and CT contributed towards more unfavorable survival outcomes.² The surgery cohort exhibited a significantly lower OS compared to the no-surgery cohort during the first 42 months of the post-operation period, possessing a 28% higher risk of death (HR=1.28; 95% CI: 1.02-1.60; p=0.03).² The OS of the surgery cohort remained slightly higher than that of its no-surgery counterpart from Month 43 to 60, yet no statistical difference was observed (p=0.15) due to both cohorts having a relatively small population (n=15 for both).² Similarly, no statistical difference was observed in the PFS of both cohorts throughout the follow-up period (HR=0.90; 95% CI: 0.72-1.11; p=0.33).²

As for safety, ePD was associated with a higher incidence of serious complications.² Patients from the surgery cohort were 3.6 times more susceptible towards Common Terminology Criteria for Adverse Events (CTCAE) Grade 3+ AEs than the no-surgery cohort (IRR=3.6; 95% CI: 2.3-5.5; p<0.001), with more than double patients experiencing ≥4 incidents of CTCAE Grade 3+ AEs compared to no-surgery cohort (18.3% vs. 7.8%).² Conversely, the no-surgery cohort was 2- to 3-times less likely to experience infections or infestations (IRR=1.99; 95% CI: 1.33-2.99), cardiac disorders (IRR=2.73; 95% CI: 1.11-6.67), respiratory, thoracic or mediastinal disorder (IRR=2.40; 95% CI: 1.52-3.80), and complications from surgical or medical procedures (IRR=2.23; 95% CI: 1.04-4.78).²

In terms of QoL, the poor outcome was more prevalent among patients who underwent ePD.² At the end of the study, the surgery cohort had a significantly lower overall EuroQol- 5 Dimension questionnaire (EQ-5D) score (MD=-0.11; 95% CI: -0.15 to -0.07; p<0.001) and Global health status (GHS)/QoL score (MD=-5.81; 95% CI: -9.73 to -1.89; p=0.004).² Significant QoL deterioration in GHS/QoL scores for physical functioning, social functioning and role functioning 6 months after treatment were observed in this cohort (p<0.001 for all three categories).²

In summary, the MARS2 trial demonstrated that the inclusion of ePD in the treatment of mPM had led to worsened survival and QoL outcomes for patients when compared to CT alone, which may imply a need for revaluation of treatment approaches for mPM.²